The overall purpose of Dr. O'Donnell's research during FY09 has been to investigate the epidemiology and genetic epidemiology of subclinical and clinically apparent atherosclerotic cardiovascular disease and its risk factors. The longer term goal is to apply these results to prediction, prevention and personalization of cardiovascular disease medicine. The major projects have emanated from the SNP Health Association Resource (SHARe), the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium, and a sequencing project conducted through the NHLBI's Resequencing and Genotyping (RSNG) Program. Dr. O'Donnell is the Scientific Director and Steering Committee Chair of the NHLBI's Framingham Heart Study (FHS) SHARe Program and he is a co-founder and Steering Committee Co-chair of the CHARGE Consortium. Research Subjects: The research subjects consist primarily of participants of the Framingham Heart Study FHS original cohort, Offspring cohort and Generation 3. Phenotyping: Phenotyping consisted of: (a) risk factor measures obtained during the usual clinical examination (lipids, blood pressure, anthropometric and physical examination);(b) biomarkers from peripheral blood (eg, C-reactive protein, fibrinogen, factor VII, von Willebrand factor, circulating bilirubin);(c) imaging measures of subclinical atherosclerosis (coronary and abdominal and thoracic aortic atherosclerosis by multidetector CT imaging (MDCT) in 3500 Offspring and Generation 3 subjects;carotid intimal medial thickness (CIMT) and carotid plaque by B-mode ultrasonography in 3800 Offspring: thoracic and abdominal aortic plaque, LV mass and LV structure by cardiovascular magnetic resonance imaging (CMRI) in 1800);(d) clinical cardiovascular outcomes (MI, myocardial infarction;CHD, coronary heart disease;CVD, cardiovascular disease) adjudicated by a physician endpoint validation committee. Genotyping in SHARe and resequencing: Genotyping derived from two dense genomewide SNP scans, a 100K SNP scan (Affymetrix platform) in 1400 FHS Offspring and original cohort subjects and a 550K SNP scan (Affymetrix platform, 250K Nsp and 250K Sty and 50K gene-focussed MIP) in 9,400 FHS subjects from all three generations. Imputation of the 550K SNPs was conducted to 2.4 million HapMap SNPs using MACH. Additionally, sequencing was conducted by the NHLBI Resequencing and Genotyping Program of 200,000 base pairs of chromosome 9p21 in 282 FHS offspring subjects. Statistical association and linkage methods: Statistical association analyses of genotypes with phenotypes were conducted using mixed linear and/or logistic regression, generalized estimating equations, and survival analyses, when appropriate;additionally, family based association testing. Statistical linkage analyses were also conducted using SOLAR. Replication Collaboration with the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium: To seek strong evidence for replication, we combined data within a consortium of prospective, observational cohort studies with genomewide SNP scans and a large, common set of phenotypes. The core cohorts include the Iceland Age, Gene/Environment Susceptibility Study, the Cardiovascular Health Study, the Rotterdam Study and the Atherosclerosis Risk in Community Study;multiple additional cohorts are collaborating from the US and Europe. In silico replication meta-analysis is performed using a common set of 2.4 million SNPs imputed to HapMap. Research Accomplishments for Major Projects Directed by Dr. O'Donnell 1. Genetic determinants of subclinical atherosclerosis: We have completed GWAS analysis of coronary artery calcification and abdominal aortic calcification and aortic valve calcium by MDCT;common and internal carotid intimal medial thickness by CIMT;and LV mass by CMRI. Several genomewide significant associations have been noted. For example, SNPs in chromosome 9p21 are strongly associated with. Replication meta-analyses have been completed in the CHARGE Consortium and manuscrripts are in preparation. In addition, Dr. O'Donnell is a collaborating investigator in GWAS analyses of cardiac ultrasound, reporting >10 new associated loci (1), and major CHD risk factor phenotypes: serum lipid levels (reported 30 loci) (2), resting systolic and diastolic blood pressure (reported >10 loci) (3,4), and obesity (5). 2. Genetic determinants of ECG phenotypes: Our group contributed to a GWAS meta-analysis was completed and reported for 10 loci underlying variation in QT interval length (6). GWAS analysis in FHS and meta-analysis in the CHARGE Consortium is underway for RR interval and QT interval. 3. Sequencing of the chromosome 9p21 region: During FY09, resequencing and analysis of resequencing data was completed in 282 FHS subjects in a 200,000 bp in the region of chromosome 9p21 implicated in MI as well as two nearby genes, CDKN2A and CDKN2B. Over 100 variants were identified and a manuscript is in preparation to describe phenotype-genotype associations of these variants in 7000 FHS subjects. 4. Genetic determinants of myocardial infarction/coronary heart disease: Dr. O'Donnell is a co-investigator in the MIGen Consortium, which reported >10 novel loci associated with MI (7). GWAS analysis has recently been conducted for incident and prevalent MI in FHS;replication analyses are underway in the CHARGE Consortium and MORGAM Cohort;and a manuscript is in preparation to describe the replication of top SNPs is underway. 4. Genetic determinants of hemostatic factors, platelet aggregability and biomarkers: GWAS analysis has recently been conducted for circulating levels of blood fibrinogen, factor VII, and von Willebrand factor, as well as platelet aggregability to epinephrine and ADP and circulating bilirubin Several genomewide significant associations were noted. Replication meta-analyses are underway in the CHARGE Consortium. A GWAS manuscript was published by us describing several genes associated with bilirubin levels (8). 5. Bioinformatics Tools: Our DIR bioinformatics fellow Dr. Johnson has created an annotated database of all published GWAS associations and demonstrated its potential use for data mining, results of which were published in an open source journal (9). He has co-developed an informatics tool with investigators at the Broad Institute, SNAP (http://www.broad.mit.edu/mpg/snap/index.php), that is now available for widespread use for defining linkage disequilibrium relationships between any two SNPs in the genome;a publication is available to describe this tool (10). 6. Epidemiology of CHD risk and coronary artery calcium: We have published a manuscript to describe the distribution and epidemiology of CAC and the potential role CAC screening has in clinical practice. We are developing an updated Framingham CHD risk score that includes CRP and family history of CHD in the model. Manuscripts for these analyses are in preparation. Selected references (out of 32 publications by Dr. O'Donnell in PubMed from October 2008 through September 15 2009) 1. Vasan RS et al. JAMA 2009;302(2):168-78. 2. Kathiresan S et al. Nat Genet 2009;41(1):56-65. 3. Levy D et al. Nat Genet 2009. Epub ahead of print. 4. Newton-Cheh C et al. Nat Genet. 2009 May 10. Epub ahead of print. 5. Heard-Costa NL et al. PLoS Genet 2009;5(6):e1000539. 6. Newton-Cheh C et al. Nat Genet 2009;41(4):399-406. 7. Myocardial Infarction Genetics Consortium. Nat Genet 2009;41(3):334-41. 8. Johnson AD et al. Hum Mol Genet. 2009;18(14):2700-10. 9. Johnson AD, O'Donnell CJ. BMC Med Genet 2009;10:6. 10. Johnson AD et al. Bioinformatics 2008;24(24):2938-9.